aParticipants in the intervention group used a computerized, interactive, decision-support guide and had access to prenatal testing with no out-of-pocket expense; those in the control group received usual care per current guidelines.

American College of Obstetricians and Gynecologists Committee on Genetics. Committee opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013;122(6):1374-1377.PubMedArticle

ImportancePrenatal genetic testing guidelines recommend providing patients with detailed information to allow informed, preference-based screening and diagnostic testing decisions. The effect of implementing these guidelines is not well understood.

ObjectiveTo analyze the effect of a decision-support guide and elimination of financial barriers to testing on use of prenatal genetic testing and decision making among pregnant women of varying literacy and numeracy levels.

Design, Setting, and ParticipantsRandomized trial conducted from 2010-2013 at prenatal clinics at 3 county hospitals, 1 community clinic, 1 academic center, and 3 medical centers of an integrated health care delivery system in the San Francisco Bay area. Participants were English- or Spanish-speaking women who had not yet undergone screening or diagnostic testing and remained pregnant at 11 weeks’ gestation (n = 710).

ResultsWomen randomized to the intervention group, compared with those randomized to the control group, were less likely to have invasive diagnostic testing (5.9% vs 12.3%; odds ratio [OR], 0.45 [95% CI, 0.25-0.80]) and more likely to forgo testing altogether (25.6% vs 20.4%; OR, 3.30 [95% CI, 1.43-7.64], reference group screening followed by invasive testing). Women randomized to the intervention group also had higher knowledge scores (9.4 vs 8.6 on a 15-point scale; mean group difference, 0.82 [95% CI, 0.34-1.31]) and were more likely to correctly estimate the amniocentesis-related miscarriage risk (73.8% vs 59.0%; OR, 1.95 [95% CI, 1.39-2.75]) and their estimated age-adjusted chance of carrying a fetus with trisomy 21 (58.7% vs 46.1%; OR, 1.66 [95% CI, 1.22-2.28]). Significant differences did not emerge in decisional conflict or regret.

Conclusions and RelevanceFull implementation of prenatal testing guidelines using a computerized, interactive decision-support guide in the absence of financial barriers to testing resulted in less test use and more informed choices. If validated in additional populations, this approach may result in more informed and preference-based prenatal testing decision making and fewer women undergoing testing.

Since the introduction of amniocentesis,1 prenatal genetic testing guidelines have focused on identifying women at increased risk of giving birth to an infant with Down syndrome or other chromosomal abnormalities, for whom invasive diagnostic testing should be recommended. Although initially advanced maternal age was the criterion for eligibility,2 identification of serum and ultrasonographic markers that can quantify the risk of an affected fetus3 led to incorporation of screening into routine prenatal care for women of all ages. The recent introduction of cell-free DNA testing has intensified the complexity of prenatal testing decision making, generating concerns about the potential for erosion of informed choice.4

Studies have questioned the “routinization” of prenatal screening and whether women understand its voluntary nature,5 and documented substantial variation in how women view the outcomes of decisions to undergo or forgo testing.6,7 Low uptake rates of invasive testing among women who receive positive screening results also have been reported,8 raising concerns about the extent to which the purpose and potential outcomes of screening are understood, particularly among women of lower literacy and numeracy levels.9 Nonetheless, clinicians continue to use risk-based approaches to counseling, often simply recommending screening and deferring conversations about further testing until screen-positive results are received.10

In this study, a randomized clinical trial was conducted of a multifaceted approach to prenatal testing designed to promote preference-based decision making. The primary goal was to assess the prenatal testing choices women make in the context of being fully informed about testing options, including having the option to forgo testing, the opportunity to engage in values-clarification exercises, and not having financial barriers. Understanding was also sought as to whether these women would make decisions characterized by greater knowledge and understanding of prenatal testing and less decisional conflict and regret.

Methods

Participants

Pregnant women who were English- or Spanish-speaking were recruited from prenatal clinics affiliated with 3 county hospitals (San Francisco General Hospital, Santa Clara Valley Medical Center, Highland Hospital [a member of the Alameda Health System]); 1 community clinic serving primarily low-income women (La Clínica de la Raza); 1 academic center (the University of California, San Francisco); and 3 medical centers of an integrated health care delivery system (Kaiser Permanente Northern California). Eligibility criteria included being less than or equal to 20 weeks of gestation with a singleton or twins and not having undergone any prenatal testing for fetal aneuploidy in the current pregnancy.

Procedures

At 2 of the sites, potentially eligible participants were sent letters describing the study with postage-paid cards offering the choice to opt in or to opt out. A bilingual research associate phoned women who did not return the opt-out card and screened those who indicated interest. At the other sites, patients were referred to an on-site bilingual interviewer who assessed interest and eligibility. After providing written informed consent, participants completed an interviewer-administered baseline questionnaire and were randomized to the intervention or control group.

A computer-generated random allocation sequence assigned participants to experimental groups within permuted blocks of random size, with a 1:1 allocation ratio, stratified by age (<35 years vs ≥35 years), clinical site, parity (nulliparous vs parous), and interviewer. Women randomized to the intervention group were provided access by the interviewer to a computerized, interactive, prenatal testing decision-support guide in their preferred language (English or Spanish) located at the interview site, and were told that after using it, the study would pay for any tests discussed for which they lacked insurance coverage. Women who were randomized to the control group received no study intervention or financial support to cover prenatal genetic testing. The protocol involved no specified interaction with any clinicians.

At 24 to 36 weeks’ gestation, patient-reported outcomes were measured during a 20-minute telephone interview. Prenatal test use was assessed postpartum via medical record review. Different research associates facilitated baseline and follow-up interviews and medical record review to ensure blinding to the randomization assignment. The randomization code was not available to any study-related personnel until data analysis was complete.

This study was approved by the institutional review boards for each site. All participants were enrolled between January 2010 and June 2012 and followed up through their deliveries, the last of which occurred in January 2013. Participants were given $40 as remuneration after each of the 2 interviews.

Experimental Intervention and Control Group

The goal of this study was to determine what women of varying literacy levels and sociodemographic backgrounds would choose after being fully informed about the benefits and risks of differing prenatal testing strategies and having the opportunity to clarify their values around these options, without the disincentive of having to pay for tests not covered by their insurance.

Women randomized to the experimental group were provided access to Prenatal Testing: Exploring Your Options, a decision-support guide created with input from a wide range of clinicians (including perinatologists, geneticists, obstetricians, nurse midwives, genetic counselors, and nurses), decision scientists, and communication and literacy experts,11 and adapted for use by women of varying literacy levels. This decision-support guide is formatted as an audio-, video-, and text-based interactive computer program narrated by a bilingual actress who speaks in a style that emulates a warm and knowledgeable friend. She emphasizes the personal nature of prenatal testing decisions, noting that the choices of forgoing testing altogether, starting with a screening test, or undergoing invasive diagnostic testing without first having a screening test, are all reasonable options, and that the goal of the program is to help the user decide on which option would be best to undertake.

Completion of the program takes approximately 45 to 60 minutes. It begins with an educational module that provides general information about prenatal testing and the role of values and preferences in prenatal testing decisions, a description of Down syndrome over the life course, more abbreviated descriptions of trisomies 13 and 18 and structural defects, and details on the diagnostic accuracy and other features of the various screening and diagnostic tests. Optional sections containing more information (titled Learn More) are included throughout this component. In the second part of the program, the user is presented with her personalized, age-related chances of carrying a fetus with aneuploidy. She is then asked to complete values clarification questions focusing on 3 decisions: (1) whether or not to have any testing; (2) if testing is desired, whether to start with screening or with invasive diagnostic testing; and (3) which specific screening and/or diagnostic test(s) to undergo. Afterwards, the user can receive graphic highlights of the testing strategy that is most consistent with the her responses, as well as click to obtain detailed information on the features of that strategy or any of the other strategies. The program concludes by encouraging the user to discuss questions with her clinician, while emphasizing that the testing strategy to undergo is her choice (see eAppendix 1 in Supplement 1 for screen shots and values clarification questions).

Women randomized to the control group received no study intervention beyond completion of the baseline and follow-up questionnaires. Consistent with current guidelines,12,13 the official policy at all recruitment sites was to offer all women, regardless of age, information on both screening and diagnostic tests and to inform them that testing was optional. However, discussions with clinicians at these sites suggested variable adherence to these guidelines, and all reported a greater focus on counseling and diagnostic testing for women aged 35 years or older.

Outcomes and Measures

The primary outcome, obtained from review of participants’ medical records, was use of invasive prenatal diagnostic testing. Secondary outcomes (also obtained from the medical record) included testing strategy undergone, as well as knowledge, risk comprehension, decisional conflict, and decision regret, measured during the follow-up telephone interview. To measure knowledge, a 15-item measure adapted from the Maternal Serum Screening Knowledge Questionnaire (eAppendix 2, Supplement 1) was used.14 Risk comprehension was assessed by asking participants to estimate, out of 1000 pregnant women who undergo amniocentesis, how many would experience a miscarriage (women reporting the risk to be >0 but ≤10 received a score of correct), and out of 1000 pregnant women their age, how many are carrying a fetus affected by Down syndrome (risks consistent with the participant’s age-related risk of Down syndrome received a score of correct). Decisional conflict and regret were assessed using 15 items from the Decisional Conflict Scale,15 and the 5-item Decision Regret Scale.16

Statistical Analysis

The primary hypothesis of this study was that women who were randomized to the intervention group would undergo invasive diagnostic testing at a lower rate than women randomized to the control group, due to better understanding of the likelihood that their fetus was affected by a chromosomal disorder and the chance that an invasive diagnostic test will cause a miscarriage, along with a greater appreciation that declining use of testing altogether is a reasonable choice.

Power analyses were conducted, partially informed by our prior research, to estimate the appropriate sample size to test this hypothesis. In assessing trends in the use of invasive diagnostic testing among women who delivered at an integrated health care system in California, this study found that the number of amniocenteses or chorionic villus sampling procedures performed as a percentage of the number of deliveries in 2006 was 12%.17 A minimal detectable difference of 6% was selected (half of the rate in the control group), corresponding to an odds ratio (OR) of 0.47 (a small to medium effect size). To achieve 80% power (2-tailed α = .05; 90% retention at follow-up), the required sample size was 396 per group or 792 in total.

Secondary hypotheses focused on patient-reported outcomes: compared with women randomized to the the control group, women randomized to the intervention group would have better testing knowledge and risk comprehension, as well as reduced decisional conflict and decision regret. The design was capable of detecting a minimum group mean difference equal to 0.21 standard deviations.

All reported analyses were based on a modified intention-to-treat sample that excluded women who reported (or whose medical record indicated) a pregnancy loss prior to 11 weeks (the earliest gestational age at which prenatal testing was available at the participating sites; none of those women were yet eligible to undergo testing). Group comparisons of 24-week outcomes were tested via linear and logistic regression, as appropriate. Analyses were reported using ORs or linear regression coefficients (b) with 95% CIs and P values. All models were fit to 20 multiple-imputed data sets created via a Markov Chain Monte Carlo method18 using SAS PROC MI version 9.3 (SAS Institute Inc). Imputation models were stratified by randomization group and included all variables represented in Table 1, Table 2, and Table 3, as well as participants’ median ZIP code income (US Census Bureau data, 2000). All parameter estimates, standard error estimates, and test statistics were calculated by combining results across the imputed data sets (2-tailed α = .05 throughout).21,22

Results

A total of 1932 women were screened for eligibility; 635 did not meet inclusion criteria (Figure). Of the 1297 eligible women, 744 enrolled in the study, a 57.3% participation rate. There were 375 women randomized to the intervention group and 369 randomized to the control group. After randomization, 34 women experienced pregnancy losses before 11 weeks’ gestation. The 710 remaining women (357 randomized to the intervention group and 353 to the control group) comprised the modified intention-to-treat sample from which the data used in this analysis were obtained.

This sample constituted a sociodemographically diverse cohort of pregnant women; 45.4% of the participants self-identified as Latina, 25.6% as white, 15.8% as black or African American, and 9.2% as Asian or Pacific Islander. Approximately one-third (35.5%) opted to participate in the Spanish-language version of the study. Nearly half (45.9%) had a high school education or less, one-fourth (25.4%) had less than adequate literacy, and 44.5% had low numeracy (Table 1).

Also as hypothesized, women randomized to the intervention group had significantly higher knowledge scores (Table 3; 9.4 vs 8.6 on a 15-point scale; b = 0.82 [95% CI, 0.34-1.31]; P < .001), were more likely to correctly report both the miscarriage risk of amniocentesis (73.8% vs 59.0% correct; OR, 1.95 [95% CI, 1.39-2.75]; P < .001), and their age-adjusted likelihood of carrying a fetus with trisomy 21 (58.7% vs 46.1% correct; OR, 1.66 [95% CI, 1.22-2.28]; P = .001). Although it was hypothesized that women randomized to the intervention group would have lower decisional conflict and decision regret, significant differences did not emerge on these outcomes.

This study accessed usage data from the decision-support guide for 325 of 357 women who were randomized to the intervention group; 309 of those women completed all sections of the program and obtained data on the testing strategy the program suggested might be most aligned with their values. For 72.2% of these women, the suggested approach was to start with a screening test; 9.7% were told that invasive testing might be the best initial approach. The remaining 18.1% were informed that their values indicated a preference for no testing. When use of the recommended testing strategy was compared with the strategy undergone among the 264 women who completed all sections of the program and for whom we had testing data, the majority (75.0%) underwent the recommended strategy.

Discussion

In a diverse population of women receiving care in a variety of settings, these findings show that after receiving complete prenatal testing information and the opportunity to explicitly consider their values and preferences via an interactive decision-support tool and having financial barriers to testing removed, participants were less likely to opt for invasive testing and more likely to forgo testing for aneuploidy altogether. This suggests that expanding coverage of amniocentesis and chorionic villus sampling to women of all risk levels may not result in increased use of these procedures. The findings also show that this approach improved patient knowledge regarding prenatal testing and understanding of amniocentesis-related miscarriage and age-adjusted risk of Down syndrome, suggesting that this intervention resulted in more informed patient decision-making.

What do the findings of this study suggest for patient counseling and decision making in an era of rapidly expanding options for prenatal testing, including cell-free DNA testing and chromosomal microarray analysis?23,24 First, this study has generated evidence that using an interactive decision-support guide that presents systematic information and an opportunity to engage in values-clarification exercises can help women of varying literacy levels make informed prenatal decisions reflective of their own preferences and goals. In addition to enabling women to consider the various options at their own pace, having such a decision guide available in clinical settings can provide a consistent and accurate message regarding the risks and benefits of testing.

This study’s finding that women who were randomized to the intervention group were less likely to undergo testing than those who received usual care adds support to the contention that women may not be receiving adequate counseling about their options. This underscores the need for clinicians to be clear that prenatal testing is not appropriate for everyone, and to present forgoing testing as a reasonable choice. With the advent of cell-free DNA testing for aneuploidy, it is particularly important that women understand the purpose and potential consequences of undergoing testing, as without adequate counseling, this new test may easily come to be viewed as simply another blood test in the large panel of routine prenatal laboratories.

Although this study was strengthened by its use of a randomized design, its focus on outcomes obtained from medical records as well as those reported by patients, and participation of English- and Spanish-speaking women of varying literacy levels receiving care in a variety of settings, several limitations deserve comment. First, while a diverse sample was successfully recruited, all participants resided in the San Francisco Bay area and the participation rate was 57.3%, potentially limiting the study’s generalizability. Participants’ knowledge and values were not measured until 24 weeks’ gestation because having women respond to those questions prior to making decisions about prenatal screening would, in itself, constitute an intervention. Therefore, this study cannot assess mechanisms of action via those potential mediators. Although a significant difference in knowledge scores emerged at this time point, the clinical significance is unclear. However, differences in knowledge scores have been shown to be strongest in the first 2 weeks after using decision tools and to dissipate over time,11 suggesting that the intergroup difference in this score may have heen higher at the time testing utilitization decisions were made. Moreover, substantive differences in the percent of women who correctly reported their likelihood of carrying an affected fetus and experiencing a procedure-related miscarriage suggests that the tool improved knowledge in these domains.

In addition, because chromosomal disorders are relatively rare (5 cases of trisomy were detected, all of which were identified via prenatal testing and resulted in terminations), there was not a sufficient sample to conduct a subanalysis of women who were found to be carrying an affected fetus. Because of the focus on observing what women would do in the context of complete information about all prenatal testing options without financial barriers, participants were told they could undergo testing without any out-of-pocket expense. How to effectively implement guides in clinical settings without such guaranteed access remains to be determined.

Importantly, this study was largely conducted before the introduction of cell-free DNA testing. As a result, no information on this new screening test was included in the decision-support guide and this option was not available to study participants. However, the general features of cell-free DNA testing and the conditions for which it screens are similar to the tests covered in this study, and the implications for counseling and informed patient decision making remain the same.

Conclusions

Full implementation of prenatal testing guidelines, using a computerized, interactive decision-support guide in the absence of financial barriers to testing, resulted in less prenatal test use and more informed choices. If validated in additional populations, this approach may result in more informed and preference-based prenatal testing decision making and fewer women undergoing testing.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kuppermann reports that she was the UCSF site primary investigator of a clinical study of cell-free DNA testing funded by Ariosa Diagnostics and receipt of unrestricted research funding from Verinata Health and Natera. Dr Caughey reports serving as a medical advisor to Ariosa and Cellscape and receipt of stock options in both companies. Dr Norton reports that she was a site primary investigator and lead coprimary investigator of a clinical study of cell-free DNA testing funded by Ariosa Diagnostics, and was site primary investigator of a clinical study of noninvasive prenatal testing funded by Cellscape; receipt of unrestricted research funding from Natera; and being an unpaid clinical advisor to Natera. No other disclosures are reported.

Funding/Support: This study was funded by grants from the National Institutes of Health (R01HD049686) and the March of Dimes Foundation (Social and Behavioral Sciences Research Grant 12-FY09-213).

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: Preliminary findings from this study were presented at the annual meeting of the Society for Medical Decision Making in Baltimore, Maryland, on October 21, 2013 (abstract TRA2-2).

American College of Obstetricians and Gynecologists Committee on Genetics. Committee opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013;122(6):1374-1377.PubMedArticle